Process for crystallizing the organic substances from steroidal origin and the thus obtained compounds

ABSTRACT

A process for crystallizing a pharmaceutically active steroidal product, without mechanical procedure, to obtain a homogeneous granulometric class which may be prepared beforehand, wherein the product which is desired to be crystallized is dissolved in a ternary mixture made of a lipophilic solvent, a hydrophilic solvent and a surface active agent at a temperature close to the boiling point of the mixture of solvents and wherein the mixture of solvents is allowed to revert to a temperature where the crystallization initiates, then, the thus-formed crystals are recovered.

This invention relates to the field of pharmacotechnology and moreparticularly it relates to a process for obtaining active ingredientsfor pharmaceutical use having a determined size of crystals, by means ofa crystallization method.

It is in fact known that the size of crystals of a pharmaceutical activeingredient plays an important role when dry or fluid pharmaceuticalformulation are realized, to insure a reproducible manufacture of theformulation and hence a constant resorption.

The fact has been frequently cited in the litterature that thevariations in the kinetics of dissolution are due either to alterationsin the crystalline structure or of the surface properties, of thecrystals, or to modifications of the extent of the surface of contactput in action (G. GILLARD Labo. Pharm. Probl. and Techn. 309 (1981)359-369).

To improve the kinetics of dissolution of the active ingredients ofdrugs showing a limited solubility, a decrease of the size of theparticles are often employed.

This problem is usually solved by the use of a mechanical proceedingsuch as grinding or micronizing (pounded by jet of air).

A study conducted on various progestatives by Muttenrauch and Cowork(STP Pharma 5(10) 1989, 642-646) has shown that the role played by thesize of the crystals on the rate of dissolution was closely linked tothe solubility of the organic substances.

It has been often disclosed on a large number of molecules oftherapeutic use, that the size of particles and the physico-chemicalproperties of the active-ingredients resulting from these treatmentsdetermine the bioavailability of the pharmaceutical formulationcontaining them through modifications of the rates and speed ofdissolution (cf. FDA paper guidelines, Manuf Control Form ANDA'S (1985).However these methods of pounding are not appropriate to pulverize allactive ingredients, some of which have low melting points and becomepasty or elastic. Other active ingredients because of their physicalproperties cannot be micronized (80% <10 μm) and this despite severalpassages in the pounder. It has been described, namely by Nakagawa andcowork (Chem. Pharm. Bull. 30 (1982) 242) that the specific surface andthe crystallinity have a great influence on the chemical stability atthe solid state, of the pulverized compound.

The rate of dissolution is also dependant up on the cristallinity of thecompound B. A. Hendricken disclosed it in Int. J. of Pharm. 60 243-252(1990). Other investigators have studied the effects of mechanicaltreatments, such as grinding, on the physico-chemical properties ofvarious active ingredients contained in the composition of apharmaceutical formulation for therapeutic purpose. These workersnoticed that the active ingredients show some alterations in thephysico-chemical properties due to these treatments.

Among them it may be cited:

loss of cristallinity (ascertained using X-rays diffraction)

variations of the specific surface SW which may become double or triple.

a drop in the chemical stability determined through differentialthermical analysis of the temperature of decomposition (for some activeingredients it has been noted drops in the melting points of 10° to 15°C.)

a variation in the surface properties which do not make always easy themanufacture of a mixture of powders. It has more precisely described inthe previously-cited Gillard's work that the morphometric, electricaland rheological properties are very significant for the realization of ahomogeneous mixture and namely these having a good flowing capacity.

All these changes in the physico-chemical characteristics on variousactive ingredients have been very precisely described by M. OTSUKA andN. KANENIWA in International J. of Pharmaceutics 62 (1990) 65-73 and inthe references cited in this article. Moreover it cannot be forgot tenthe influence of the decrease in the size of the particles produced bygrinding on the hardness of tablets obtained from these compounds (cf.Y. SAGAWA J. Powder Technol. Jap. 20 (1983) 737-743).

This is why the experimental results from Tawashi (STP Pharma. 6(5)(1990) 299-302) supplied with an illustration of the relation-ship whichexists between decrease in the size of the particles and morphologicalaspects of thus resulting fragments. The result of the mechanism ofreduction in the size depending on the utilized means on themeasurements of the fragments substantially relate to the evidence ofthe irregularity of the surfaces of the particles and the relation-shipwhich exist between the surfaces and physical behaviour of powdersduring the manufacture of pharmaceutical formulations. Throughappearance of the surface, through its influence on the capacity offlowing of the product, constitutes one of the significant factors whichhave an influence on the qualities of a mixture of powders in order torealize such a pharmaceutical formulation. The effect of the mechanismof reduction in the size also plays an important role on the solubilityof the active ingredient.

Other studies have moreover shown that the crystalline form of an activeingredient could still undergo a transformation (crystallisation) or adeformation (such a plastic) during the compression (cf. C. FUHRER, STPPharma. 6(5) (1990) 294-298).

The grinding may also results in replacing the crystals withagglomerates equivalent to smaller crystals, which do not improve in anymanner neither the solubility nor the rate of dissolution of the activeingredient.

Moreover a grinding when mechanical as it is the case with crusher withknifes, may introduce some dirts of the products with metallic particlesor with oil.

This invention has then as a subject matter to find a solution which ismore satisfactory than the grinding, to obtain a granulometric range ofcrystals which may be used in the pharmaceutical industry whileachieving at will, crystals of a determined size with a quasi constantpercentage and which avoids the use of damaging methods for the decreaseof the size of particles such as the various publications mentioned andsuch as the applicant itself, could state it on the experienced activeingredients.

It appeared thus possible to arrive to a solution of this physicalproblem relating to crystallization and to obtain in this way ahomogenous granulometric class of crystals without it would be necessaryto have recourse to a grinding or to a sieving and without evenmodifying the cristalline system of the starting material. This has beenascertained through microscopy and thermal differential analysis (TDA).

The applicant has then searched, to avoid the use of a proceeding ofgrinding, to exert an influence on the various parameters which controlthe phenomena of crystallization and namely to modify the constituentsof the mass to be crystallized. These procedures have as a goal to exertan influence namely on decisive parameters such as mass transfers andheat transfers. It is known, in fact, that mass transfer is due to aphenomenon of diffusion of the molecules from the liquid mass to thesurface of the crystals and that heat transfer is caused by thediffusion of the heat of crystallization (energy of binding releasedduring the period of formation of the crystal) from the surface ofcrystals to the mass of liquid. A sufficient command of thesurimposition of both transfers allows to exert an influence on thegrowth of the crystals and this to avoid the factor of vicinity ofcrystals during their formation in concentrated solution.

The latter parameter intervenes for disturbing the regular growth ofcrystals while causing the formation of agglomerates.

This invention has then as a subject matter a process for crystallizingwhich through this influence on the parameters of crystallizationauthorizes without mechanical proceeding, to obtain a homogeneousgranulometric range according which the product which is to becrystallized is as a preliminary, dissolved in a ternary mixture made ofa lipophilic solvent, a hydrophilic solvent and a surfactant, at atemperature near the boiling point of the mixture of solvents and theresulting solution is cooled to a temperature, where the crystallisationinitiates, the thus-formed crystalls which are of the same crystallinesystem as those at first utilized before they are dissolved in themixture of solvents but are of the desired size.

Similar processes, except they are in a binary mixture, have alreadybeen described for recrystallizing mineral salts such as for exampleCHIANESE A and cowork. Process Technol. Proc. 89--Vol. 6 (ind. cryst.87) 261-264 such as sodium perborate, wherein the said authors use asurfactant in water, to recrystallize the said salt, or BLASZCZAK J. andcowork. Kryst. Przem. Krajowe Symp. Mater Konf. 3rd (56 WYAM) 89--95-101on hydrated Aluminium fluoride.

In the litterature they are also found many publications which study thecrystallization to obtain the active ingredients in a well-definedcrystalline system, such as for example G.A.J.M.T Sas and cowork whichuse a process through precipitation to obtain an active ingredientcrystallized in the monoclinic system (Eur. Pat. Appl. 389.035) or thento resolve polymorphic forms such as Terfenadin (2 crystalline forms)cf. T. G. Fawcett and al. (U.S. Pat. No. 4,742,175) other scientistshave prepared microcrystalls by precipitation in an "anti-solvent"-Schmitt W. achieves this process for microcrystallizing, in dissolvingthe active ingredient in a hydrosoluble solvent and injecting theaqueous solution into cold carbon dioxide- Microcrystals are thusobtained (PCT Int. Applic. WO 90/03782--CA (1990) 113, 178284 k).

In the process according to this invention, the hydrophilic solvent isselected in such a manner to be miscible or soluble in the lipophilicsolvent, to insure a homogeneous solution. Preferably the hydrophilicsolvent is an aqueous mixtures of solvents and more particularly wateradded to a polar solvent and/or a lower alkyl ester.

After numerous searches it appears to be advantageous to select from thefamily of alkanols (i.e. methanol, ethanol, butanol, isopropanol), ofketons (such as acetone, methylethylketone, and methyl isobutylketone)ethyl acetate, isobutyl acetate inter alia and water, the percentage ofwhich in the binary mixture ranges between 0 and 12%.

The surfactant is preferably a anionic surfactant selected among thepolyoxy ethylenic esters of sorbitan and fatty acids having at least 8carbon atoms, the polyoxy ethylenic ethers of fatty alcohols having atleast 8 carbon atoms and the polyoxy ethylenic esters of stearic acid.

The anionic surfactant is selected among those which have an amphiphiliccharacter, but with a predominant hydrophilic character having a HLB>12,such as for example the polyoxy ethylenic esters of sorbitan and a fattyacid such as the TWEENS 20 to 40, the polyoxy ethylenic ethers of fattyalcohols such as the BRIJ 56, 58, 78, 96, 97, 98 and 99, G 3816 and3820, G 3910 and 3920 or ETHYLAN D 254 to 257, RENEX, CREMOPHOR or ofthe type PLURONIC (F 68).

The polyoxy ethylenic esters of stearic acid such as the MYRJS 49, 51,52, 53 and 59 are also suitable because they further improve thedissolution of the active ingredients, they allow to getvery-concentrated solutions during the crystallization and to decreasealso the, temperature of recrystallization for obtaining thesupersaturation of the medium.

As a function of the series of active ingredients to be used, it appearsadvantageous to utilize a ternary mixture consisting of the previouslycited solvents containing from 1 to 12% water and 0,01 to 10% of thesurfactant and most preferably from 0.05 to 5%.

This ternary mixture may be produced at once or through severalsuccesive steps in dissolving first the active ingredient in one of thesolvents, in adding optionally the surfactant then in making completethe mixture with the other solvent. The volume and the nature of theternary mixture to be used for the recrystallization, will be selectedas a function of the granulometric class to be searched for the studiedpharmaceutical form and as a function of the expected yield.

For a definite active ingredient, it will be necessary to establish aternary diagramm of the mixture to be used and to define the proportionof the solvents which constitute this mixture.

The volume of the ternary mixture depends on the solubility of theactive ingredient at reflux temperature in this mixture. A goodsolubility is required to obtain relatively high concentrations in themass since this one is an influent factor of the growth of the crystalsin the course of cooling.

The presence of water is necessary for some surfactants to insure a goodrepartition of these ingredients in the liquid mass and thus to promoteits incorporation in the network, to form liquid and solid masses in thecourse of recrystallization and thus to influence the interfacialtension liquid/solid. The effect of vicinity in the course ofcrystallization may disturb the regular growth of the crystals and leadto groupings having not any clear shape. It is merely the well ordereddisposal in the space of the particles composing it, which distinguishthe crystals from the amorphous substances wherein the arrangement ofthe particles is anarchic.

The temperature of heating of the ternary mixture plays an importantrole. The ternary mixture containing the active ingredient to becrystallized, is lead to a temperature as close as possible from theboiling point of the said mixture in order to insure an highconcentration of the substance to be crystallized and in order to be ina position to decrease at most as possible, the temperaure ofrecrystallization of the said substance.

The size of the thus obtained crystal also varies as a function of theconcentration and the ratio lipophilic solvent/hydrophilic solvent. Theamount of hydrophilic solvent goes through an optimal value such as forexample with the progestative derivatives, between 2 a 5% in thepresence of a solvent of the ketonic kind such as methyl ethylketone toobtain a class of crystals the granulometry of which lies between 35 and70 μm and preferably around 5% to restrict this class between 35 and 55μm.

With 7.5% of the previously used solvent, the class of crystals raises anew to between 70 and 100 μm. This increase in the content ofhydrophilic solvent leads to crystals with higher size. Moreover whenoperating in a more or less diluted medium, the crystals are caused tobe of more or less extended size and to be a function of the nature ofthe utilized tenside. It appears that the general rule according towhich, smaller crystals are obtained if the concentration of the activeingredient is more significant in a medium of crystallization containingonly one solvent, is not always verified in this process ofcrystallization.

The rate of cooling, the temperature of initiation of therecrystallization, the nature of the ternary mixture and theconcentration of the active ingredient, are the parameters needed forthe selection of a determined granulometry. The cariage of frigories aswell as the stirring of the medium will have to be previously definedfor each study. The isolation of the active ingredient by filtration isto be carried out at temperatures which may range from +45° to -10° C.

The scale up of this process in the industry for particular compounds,gave rise to some shifts in the granulometric classes. For example forPromestriene at the level of 1 g, crystals of about 50 μm have beenobtained, whilst for a batch of 60 kg the same experimental conditionssupplied crystals with a granulometry of about 150 μm. Accordingly anadjustment is required when the process has to be adapted to theindustrial production.

The active ingredient to be crystallized is preferably a compound havinga steroidal structure and particulary a derivative of estraneandrostane, pregnane, 19-nor pregnane and cholestane.

Among the derivatives of estrane, it may be cited estradiol, estrone,estriol, 19-nor Testosterone as well as their esters and/or theirethers. A more precise example of derivative of estrane is the 3-propylether of the 17-methyl ether of estradiol (Promestriene) or 19-norTestosterone, Undecanoate.

Among the derivatives of androstane, it may be cited Testosterone, itsethers and ethers in position 17, the substituted Testosterone inposition 4,6,7 or 16 such as for exemple 4-chloro Testosterone, 6-methylTestosterone, 7-methyl Testosterone, the fatty acid esters ofTestosterone such as Testosterone cyclopentyl acetate or cyclohexylpropionate, the derivatives of androsta 2-ene substituted in position 17such as 17-β-acetoxy-17α-ethynyl-5α-androsta-2-ene.

Among the derivatives of pregnane it may be cited progesterone, itsenolic ethers, the cyclic or linear enamines, the 17α-hydroxyderivatives thereof, the esters of 17α-hydroxy progesterone, theprogesterones substituted in position 1, in position 6, in position 7 orin position 16.

Among the 21-hydroxy pregnenic derivatives, it may be cited thecortisone derivatives such as cortisone, cortisol, prednisone, medrol,dexamethasone, β-methasone or Triamcinolone.

Among the derivatives of 19-nor progesterone it may be cited 17α-hydroxy19-nor progesterone, its ethers in position 17, its esters in position17 as well as the substituted 19-nor progesterones such as 6-methyl17α-hydroxy 19-nor progesterone, its ethers in position 17, its estersin position 17, as well as 6-methyl-3,20-dioxo-17α-hydroxy19-nor-pregna-4,6-diene and its esters.

Among the cholestanic derivatives it may be cited the biliary acids,cholesterol and its esters, ergosterol, stigmasterol and Calciferol.

The micro-crystalline compounds obtained according to the process ofthis invention are use ful active ingredients of dry pharmaceuticalcomposition such as uncoated tablets, tablets with slow release, softgelatine capsules, granulates; or in liquid pharmaceutical compositionssuch as drinkable suspension or injectible suspensions for intramuscularor intra-articular administration, in vaginal preparations such assuspension, bio-adhesive gels, suppositories or vaginal suppositories.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-21 are illustrative of the various test results from theexamples. FIG. 1 illustrates the transition enthalpy for solid/liquidtransitions of the microcrystallized product. The differential thermicanalysis of the raw product, ground product, and microcrystallizedproduct are shown in FIGS. 2-6. FIGS. 7, 11, 12, 15 and 16 show theresults of granulometric analysis as determined by a laser granulometerCoulter LS 130. Results of differential thermic analysis of Nomegestrolacetate, before and after grinding, are illustrated by FIGS. 8 and 9,respectively. FIGS. 13 and 14 demonstrate the chromatographic analysisby HPLC of Nomegestrol acetate, before and after grinding, while FIG. 10illustrates the thermogravimetric analysis of the starting material.FIGS. 17-20 show the granulometric analysis for batches 23, 27, 33 and35, respectively. (See Example XII) FIG. 21 is a comparison of thedissolution curves.

The following examples illustrate this invention without limiting it inany manner. They show the interest of this process in comparison withthe conventional grinding.

EXAMPLE I Microcrystalls of Hydrocortisone

10 g of hydrocortisone are dissolved at reflux temperature in 10 volumesof a solvent mixture formed of:

95.8% methylethylketone

4% water

0.2% Tween 20

It is kept to reflux for 5 to 10 mn under stirring and it has to be sureit no longer remain any particle suspended. Under stirring, the mass iscooled to -10° C. This temperature is maintained for one hour and theresulting crystals are dried. The crystals are washed with water andfurther dried under reduced pressure, at a temperature close to 50°-60°C. The thus formed crystals are of 25×30 μm for the biggest ones to 5×10μm for the smallest ones.

MPk: 221.5°-222° C.

[α]_(D) (methanol)=+156°±2°

EXAMPLE II Microcristalls of Dexamethasone Acetate

10 g dexamethasone acetate are dissolved at reflux temperature in 4 vol.of a solvent mixture made of:

89.0% methylethyl ketone

10.5% water

0.5% MIRJ 51

The reflux is kept for 30 mn. The insoluble particles are filtered andthe filtrate is cooled to -15° C. This temperature is maintained for 1hour before drying the crystalline mass. The crystals are washed withwater then dried at 60° C. under reduced pressure. The size of the thusformed crystals extends from 80×50 μm for the biggest ones to 8×10 μmfor the smallest ones.

MPk=226°-227°

[α]_(D) (methanol)=+84°±2°

EXAMPLE III Microcrystalls of Dexamethasone Acetate

10 g of Dexamethasone acetate are dissolved at reflux temperature into 4vol. of a solvent made of:

87.6% acetone

12.0% water

0.4% TWEEN 20

Isolation is carried out as described in the preceding example andcrystals are obtained the range of which extends from 200×75 μm for thebiggest ones to 160×50 μm for the smallest ones.

MPk=228° C.

[α]_(D) (methanol)=+86°±2°

EXAMPLE IV Microcrystalls of Prednisone

10 g prednisone are dissolved in 5 vol. of a solvent mixture made of:

94.8% methylethyl ketone

5.0% water

0.2% TWEEN 20

Isolation of the crystals is performed as described in the foregoingexamples (cooling to -10° C.). It is obtained crystals the maximum sizeof which, is about 55×40 μm and the minimal size of which is 35×24 μm.

MPk=240°±1° C.

[α]_(D) (methanol)=+167°±4°

EXAMPLE V Microcrystalls of Nomegestrol Acetate

10 g Nomegestrol acetate are dissolved at the reflux temperature in 6Vol. of a solvent mixture made of:

94.9% methanol

5.0% water

0.1% TWEEN 20

The temperature is let to revert very slowly under stirring usingexternal cooling to -5° C. This temperature is maintained for 15 mn. Thecrystalline mass is separated, dried then washed with water and driedagain under reduced pressure.

The thus-formed crystals range from 50×25 μm for the bulkiest ones to10×10 μm for the smallest ones.

EXAMPLE VI Microcrystalls of Nomegestrol Acetate

The procedure of example I is followed but using 2 vol. of a ternarysolvent mixture made of:

92.4% methylethyl ketone

7.5% water

0.1% TWEEN 20

The microcrystals are recovered, the size of which ranges from 100×100μm for the bulkiest ones to 65×35 μm for the smallest ones.

EXAMPLES VII Microcrystalls of Nomegestrol Acetate

The same procedure than at example I is used but utilizing 2 vol. of aternary solvent mixture made of:

94.9% methylethyl ketone

5.0% water

0.1% TWEEN 20

The microcrystals are recovered, the size of which ranges from 55×40 μmfor the bulkiest ones to 35×25 μm for the smallest ones.

EXAMPLE VIII Microcrystals of Nomegestrol Acetate

The same procedure than at example I has been used but using 2 vol. of aternary solvent mixture formed of:

87.9% methylethyl ketone

12.0% water

0.1% TWEEN 20

The microcrystals are recovered, the size of which ranges from 150×65for the bulkiest ones to 90×50 μm for the smallest ones.

EXAMPLE IX Microcrystalls Of Nomegestrol Acetate

The same procedure than at example I is used but utilizing 1,5 vol. of aternary solvent mixture made of:

94.9% methylethyl ketone

5.0% water

0.1% TWEEN 20

The microcrystals are recovered the size of which ranges from 120×40 μmfor the bulkiest ones to 75×50 μm for the smallest ones.

EXAMPLE X Microcrystalls Of Promestriene

The same procedure than at example I is used but dissolving one part ofPromestriene in 4 vol. of a ternary solvent mixture made of:

94.9% ethanol at 100%

5.0% water

0.1% TWEEN 20

The crystals are recovered, the size of which ranges from 300×100 μm forthe bulkiest ones to 100×50 μm for the smallest ones.

EXAMPLE XI Microcrystalls Of Promestriene

The same procedure than at the fore going example has been followed indissolving 30 kg Promestriene in 3 vol. of a ternary solvent mixturemade of:

    ______________________________________                                        94.8% methylethyl ketone                                                                            (i.e 85.320 l)                                           5.0% water           (i.e 4.500 l)                                            0.2% TWEEN 20        (i.e 0.180 l)                                           ______________________________________                                    

The mixture is cooled to -10° C. After 15 mn at this temperaure, thethus-formed crystals are filtered. They were washed with water and driedin a oven at about 35° under reduced pressure. The thus recoveredcrystals have a size which ranges from 125×100 μm for the bulkiest onesto 80×50 μm for the smallest ones.

The compounds which have been used for these studies (raw compounds,ground compounds and microcrystallised compounds) have been controlledthrough differential thermic analysis.

Separated studies comparing a raw product and a ground product (Ref.C.114 and C.114B) comparing two ground compounds (C.108B and C.114B) andcomparing a raw compound and a microcrystallized product (C.109 andC.109M) have given the following results:

between the tested products from the batches C.108B, C.114B and C.114 insimilar experimental conditions in the field of temperatures rangingfrom 12° to 142° C., these three compounds show through differentialthermic analysis with temperature scanning, similar behaviours (seeFIGS. 2,3,4,5 and 6).

The melting of these compounds appears to be similar between them, withtemperature located in the neighborhood of 64° C. and a melting enthalpyranging from 72 to 74 joules/g.

The microcrystallized product has a melting temperature of 64.57° C. andmelting enthalpy located at 73.2 joules/g, thus very close to that ofthe other compounds.

EXAMPLE XII Microcrystalls of Nomegestrol Acetate

Two assays of crystallization have been carried out along the procedureof this invention, starting from 30 kg of Nomegestrol acetate.

The starting material is dissolved in 4 vol. of a ternary solvent madeof:

94.9% methanol

5.0% water

0.1% TWEEN 20

The resulting crystalline product is recovered and shows thegranulometric range as follows (as determined with a laser granulometerCoulter LS 130):

assay 1: batch 037 MC 2

assay 2: batch 037 MC 3 (see FIG. 7)

For these two assays the results are statistically similar for adefinite granulometric range, all the particles of which are inferior to400 μm.

On the contrary when grinding various industrial batches, it has beenstated a large irregularity in the range of the granulometric classes(cf. curves of the batches 23, 27, 33 and 35 in FIGS. 17 to 20).

EXAMPLE XIII

Assays have been performed on larger patches of Nomegestrol acetateusing 40, 60 and 90 kg respectively, according to the proceduredisclosed in example XII. The results have been as good as the precedingones.

Even an assay with 90 kg (Ref. S4-- batch 3) has given the followinggranulometric analysis (see FIG. 16).

EXAMPLE XIV Microcrystalls of Progesterone

This study has been performed as in the preceding examples, bydissolving the starting material at the reflux temperature in 6 vol. ofa solvent made of:

93.4% ethanol

6.0% water

0.6% TWEEN 40

The thus formed crystals are separated in the cold and washed with waterthen dried. The thus produced crystalls range from 150×80 μm for thebulkiest ones to 10×20 μm for the smallest ones.

MPk=125°±2°

[α]_(D) (dioxan)=+170°±4°

EXAMPLE XV Microcrystalls of 17β-Acetoxy 17α-Ethynyl 5α-Δ2-Androsten

As described in the preceding examples, the product has been processedin dissolving it at the reflux temperature in 4 vol. of a mixture madeof:

96.0% ethyl acetate

3.2% water

0.8% TWEEN 20

The crystals are recovered as previously described in the precedingexamples. The thus produced crystals has a mean granulometry of 40 to 60μm.

MPk=125°-129°

EXAMPLE XVI Microcrystalls of Androstanolone (4-Dihydro Testosterone)

The product is processed as in the previously cited examples, indissolving the starting material at the reflux temperature in 7.5 vol.of a solvent made of:

91.8% methanol

8.0% water

0.2% TWEEN 20

The thus formed crystals are separated in the cold, then are washed withwater and dried. The crystals show a mean granulometry of 120 μm.

MPk=182°±2°

[α] (ethanol)=+30°±2°

A differential thermic analysis has been performed on industrial batchesof Nomegestrol acetate before grinding, after grinding and aftermicrocrystallization:

sample A and B for Nomegestrol acetate before grinding (FIG. 8)

sample C and D for Nomegestrol acetate after grinding (FIG. 9)

samples E and F for Nomegestrol acetate after microcrystallisation

The microcrystallization, subject of this invention, has been performedon the raw material before grinding.

RESULTS

The assays temperatures range from 290° to 525° K. It has not been foundany solid/solid transition. The solid/liquid transition has been founddepending on the sample from 178.1° to 179.1° C.

The transition enthalpy is about 6.8 joules/g. The intervals oftemperature for the transitions solid/liquid have been found thesmallest for the samples E and F, resulting from the microcrystallizedcompound according to the therein claimed process (FIG. 1).

A thermogravimetric analysis has been performed on a sample (B) ofstarting material. With this kind of product at assay temperaturesranging from 25° to 700° C., the loss of mass is about total at 400° C.(FIG. 10).

It has been also possible to study the granulometric classes resultingfrom the process of microcrystallization, by means of an image scannerfitted with a logiciel VIDS IV.

On the industrially recrystallized product according to the process ofexample XII (batch 037 MC 2) it has been performed a study with thiskind of material. The obtained results are expressed in μm for thedimensions (parameters and length) and in μm² for the surfaces.

This kind of analysis allows a clear confirmation of the resultsobtained by Laser granulometry. In a field of small particles, it hasbeen made out particles from 9 to 16 μm, which are values similar tothat observed by Laser granulometry.

Analysis of the bulkiest particles has supplied with dimensions close to70 μm, values also obtained with Laser granulometer.

The chromatographic analysis by HPLC allows to show the banefulinfluence of the grinding. For Nomegestrol acetate the damaging may beevaluated to about 0.2%.

Some examples of industrial batches evidence this phenomena:

batches before grinding (Ref. 028 and 031)--(see FIG. 13)

batches after grinding (Ref. 028B and 031B)--(see FIG. 13)

The analysis by HPLC have been carried out at two disterict wawelenghthes (245 and 290 nm) to have a better separation of the impuritiesof the type 3-keto Δ-4 pregnene from that of the type 3-ketoΔ4,6-pregnadien.

To overcome this damaging, several methods have been contemplated:

one consisting in grinding while cooling the apparatus

the other one using the method of crystallization according to thisinvention.

In order to be comparative and to be able to validate the methodaccording to this invention, both techniques have been put into practiceon a same batch of active ingredient ##STR1##

The batches designated as 037-MC 1 a 3 are three assays ofrecrystallization on industrial batches (30 kg) in order to confirm thevalidity of the disclosed method, as regard to the granulometric class(FIGS. 7,11 and 12).

The HPLC analysis on the so produced compounds have been performed underthe same conditions than those previously described.

These tests fully demonstrate that:

the grinding, even performed under cooling, does not prevent that thecompound fall into disrepair (cf. FIG. 14).

the crystallization according to the process of this invention, allowsto obtain an active ingredient of better quality and that in the wantedgranulometric class without the need to recurse to a grinding method(FIG. 15).

This phenomenon of chemical alteration is also stated on other steroidalcompounds to a more or less extent, depending on the considered activeingredient.

The following examples related to formulations illustrate the use of themicrocrystallized compounds of this invention and more particularly ofthe compounds derived from pregnane.

The disclosed granulometric class is the most representative of thecited compound (i.e.>80%).

EXAMPLE XVII Tablets with Belated Release

Unit formulation for various dosologies

    ______________________________________                                        microcrystallized Nomegestrol acetate                                                               1.25 to 10.00                                                                             mg                                          (200 to 300 μm) from                                                       Aerosil 200           0.37 to 0.50                                                                              mg                                          Precirol ATO 5        1.85 to 2.25                                                                              mg                                          Methocel E.4          55.0 to 70.00                                                                             mg                                          Avicel PH 101         10.00 to 20.00                                                                            mg                                          Lactose enough for 1 tablet of                                                                      185.00 to 200.00                                                                          mg                                          ______________________________________                                    

EXAMPLE XVIII Tablets with Fast Release

Unit formulation for various dosologies

    ______________________________________                                        microcrystallized Nomegestrol acetate                                                               1.25 to 10.00                                                                             mg                                          (<50 μm)                                                                   Aerosil 200           0.37 to 0.50                                                                              mg                                          Precirol ATO 5        1.85 to 2.00                                                                              mg                                          Avicel PH 102         50.00 to 70.00                                                                            mg                                          Explotab or Polyplasdone XL                                                                         5.00 to 25.00                                                                             mg                                          Lactose enough for a tablet of                                                                      185 to 225.00                                                                             mg                                          ______________________________________                                    

EXAMPLE XIX Tablets of Nomegestrol Acetate

Unit formulation for various dosologies

    ______________________________________                                        microcrystallized Nomegestrol acetate                                                               1.25 to 10.00                                                                             mg                                          (200 to 300 μm)                                                            Aerosil 200           0.37 to 0.50                                                                              mg                                          Precirol ATO 5        1.85 to 2.25                                                                              mg                                          Avicel PH 101         55.00 to 70.00                                                                            mg                                          Lactose enough for a tablet of                                                                      185.00 to 220.00                                                                          mg                                          ______________________________________                                    

The analysis of the results by the function of distribution ofWeibull(D. GIBASSIER and COWORK--STP PHARMA 1(10) (1985) 967-973)evidence a significant difference between these three formulations.

The shapes of dissolution curves, as shown by the parameter β of thisfunction, give 0.148 for a formulation with fast release, 1.015 for aformulation with normal release and 1.914 for a formulation with delayedrelease (cf. FIG. 21).

The process of this invention thus allows the realization ofgranulometric classes of an active ingredient appropriate to the needsof the formulation to be realized.

It is ascertained that these two pharmaceutical compositions which havebeen realized from industrial raw materials, have an equivalentbioavailability.

EXAMPLE XX

Injectible depot formulation based on Medroxyprogesterone or onNomegestrol in the form of their acetates.

Unit formulation for 1 flask of 5 ml:

    ______________________________________                                        microcrystallized Medroxy progesterone acetate                                                          500.00  mg                                          or microcrystallized Nomegestrol acetate                                      (15 to 40 μm)                                                              Polyethylene glycol 4000  200.00  mg                                          Preservatives             0.006   mg                                          Sodium chloride/Sodium Citrate                                                                          0.15    mg                                          Distilled water for injection                                                                           5.00    mg                                          ______________________________________                                    

EXAMPLE XXI Vaginal or Gynaecologic Capsule

a) unit formulation for a capsule

    ______________________________________                                        microcrystallized progesterone                                                                      50 to 500.00                                                                             mg                                           (200 to 300 μm)                                                            Vaseline (pharmacopeia)                                                                             200.00     mg                                           Sorbitol sesquioleate 200.00     mg                                           Synthetic perhydrosqualene                                                                          1.85       g                                            ______________________________________                                    

Dry coating: gelatine, glycerol, preservative, for a soft gelatinecapsule weighing 2.55 g

b) vaginal suppository

    ______________________________________                                        microcrystallized Nomegestrol acetate                                                                    20.00  mg                                          vithepsol H35 or H37 enough for a suppository of                                                         2.8    g                                           ______________________________________                                    

EXAMPLE XXI Bioadhesive Gel for Cutaneous or Gynaecologic Use

Formula for 100 g:

    ______________________________________                                        microcrystallized Progesterone                                                                       2.0 to 3.0                                                                             g                                             Polyethylene glycol    4.0 to 6.0                                                                             g                                             Carboxypolyvinyl polymer                                                                             0.5 to 1.0                                                                             g                                             Preservatives          0.3      mg                                            Triethanolamine enough for pH 6.5                                             Purified water         100.0    g                                             ______________________________________                                    

EXAMPLE XXIII Bioadhesive Gynaecologic Foam Formula for a Dispenser (2.5ml) of 50 g

    ______________________________________                                        microcrystallized Progesterone                                                                       2.0 to 5.0                                                                             g                                             Carboxypolyvinyl polymer                                                                             0.5%                                                   Isobutane              5.5%                                                   Excipient base F25/1 enough for                                                                      50.0     g                                             ______________________________________                                    

Shake the suspension before use.

Dispensed dosage from 100 to 250 mg.

EXAMPLE XXIV Implants

Formulation for 100 g of material to be extruded:

    ______________________________________                                        Nomegestrol acetate        5.0 g                                              Poly (orthocarbonates) enough for                                                                       100.0 g                                             ______________________________________                                    

The temperature of the mixture shall not excede 185° C. in order not toimpair the crystalline form of the active ingredient.

EXAMPLE XXV Intra-uterine Device with Reservoir

Device with a Silastic reservoir of 2.5 to 3.5 cm length for a thicknessof 0.4 to 0.8 mm and a diameter of 2 mm.

The preparation is formulated as a suspension as follows:

For 100 g of suspension:

    ______________________________________                                        microcrystallized Progesterone (80-250 μm)                                                         0.600 to 1.0                                                                            g                                           suspended into                                                                suspending agent        0.5       g                                           synthetic Perhydrosqualene                                                                            100.0     g                                           ______________________________________                                    

EXAMPLE XXVI Patches

Content of the reservoir. Preparation for 100 g:

    ______________________________________                                        microcrystallized Nomegestrol acetate                                                                   0.5    g                                            (80-250 μm)                                                                Carboxy polyvinylic polymer                                                                             0.2    g                                            Colloidal silica          0.2    g                                            Silicone oil enough for   100.0  g                                            ______________________________________                                    

Examples of Formulation of Estrane Derivatives EXAMPLE XXVII Tablets

Unit formulation:

    ______________________________________                                        microcrystallized Estradiol (10-50 μm)                                                            1.0 to 2.0 mg                                          Kollidone 25           10.0 to 20.0 mg                                        Kollidon 90             5.0 to 10.0 mg                                        Avicel PH 102          25.0 to 50.0 mg                                        PEG 6000               1.0 to 2.0 mg                                          Precirol ATO 5         1.5 to 3.0 mg                                          Polyplasdone XL        2.5 to 5.0 mg                                          Lactose enough for 1 tablet                                                   ______________________________________                                    

EXAMPLE XXVIII Bioadhesive Gels based on Estradiol or Promestriene

Formulation for 100 g of gel:

    ______________________________________                                        microcrystallized Estradiol or Promestriene                                                           1.0 to 2.0                                                                              g                                           Propylene glycol        5.0 to 10.0                                                                             g                                           Carboxypolyvinyl polymer                                                                              0.5 to 1.0                                                                              g                                           Preservatives           0.3       mg                                          Triethanolamine enough for pH                                                                         6.0 to 6.5                                            Purified water enough for                                                                             100.0     g                                           ______________________________________                                    

EXAMPLE XXIX Vaginal Capsules

Formulation for one capsule:

    ______________________________________                                        microcrystallized Estradiol                                                                           1.0 mg                                                Labrafil M 1944 CS      0.5 g                                                 Perhydrosqualene        1.3 g                                                 ______________________________________                                    

Dry coating: gelatine, glycerol, preservatives for a soft gelatinecapsule of 2.1 g

EXAMPLE XXX Patches

Content of the reservoir: formula for 100 g

    ______________________________________                                        microcrystallized Estradiol (80-100 μm)                                                            0.5 to 1.0                                                                             g                                            Aerosil                 0.5      g                                            synthetic Perhydrosqualene enough for                                                                 100.0    g                                            ______________________________________                                    

EXAMPLES OF FORMULATION WITH COMPOUNDS DERIVED FROM ANDROSTANE EXAMPLEXXXI

Formulation as tablets-unit formulation for a 380 mg tablet:

    ______________________________________                                        microcrystallized 17β-acetoxy 17α-ethynyl                                                    20.0    mg                                          5α-androst-2en                                                          Avicel PH 101             91.20   mg                                          Aerosil                   0.45    mg                                          Precirol ATO 5            7.60    mg                                          Explotab                  4.30    mg                                          Lactose                   256.45  mg                                          ______________________________________                                    

This formulation shows a better availability than that previouslydisclosed in the literature.

EXAMPLE XXXII Gynaecologic Gel

Formulation for 100 g:

    ______________________________________                                        microcrystallized Androstanolone                                                                      2.50    g                                             (dihydrotestosterone)                                                         Propylene glycol        2.50    g                                             Transcutol              5.00    g                                             Preservatives           0.08    g                                             Viscosity agent (such as TEA)                                                                         0.25    g                                             Carboxypolyvinyl polymers                                                                             1.50    g                                             Purified water enough for                                                                             100.00  g                                             ______________________________________                                    

EXAMPLE XXXIII Oral Capsule

    ______________________________________                                        microcrystallized Testosterone Heptylate                                                                50.00 mg                                            Oleic acid enough for 1 capsule                                                                        250.00 mg                                            ______________________________________                                    

Coating: gelatine, preservatives, glycerol

EXAMPLES OF FORMULATION WITH COMPOUNDS DERIVED FROM 21-HYDROXY PREGNENESEXAMPLE XXXIV Tablets for the Oral Way

Unitary formulation for each tablet:

    ______________________________________                                        microcrystallized Prednisone (80-150 μm)                                                            2.50    mg                                           Avicel PH 102            50.00   mg                                           Aerosil                  1.80    mg                                           Precirol ATO 5           2.00    mg                                           Lactose enough for one tablet                                                                          128.70  mg                                           ______________________________________                                    

EXAMPLE XXXV Tablets for the Oral Way

Unitary formulation for each tablet:

    ______________________________________                                        microcrystallized Prednisone (80-150 μm)                                                             0.50   mg                                           Avicel PH 102             50.00  mg                                           Aerosil                   1.70   mg                                           Precirol ATO 5            2.00   mg                                           Lactose enough for on tablet                                                                            130    mg                                           ______________________________________                                    

EXAMPLE XXXVI Gel for Cutaneous Application

Formulation for 100 g:

    ______________________________________                                        microcrystallized Dexamethasone acetate                                                               0.05 to 0.10                                                                            g                                           Polyethylene glycol     5.00      g                                           Carboxypolyvinyl Polymer                                                                              1.00      g                                           Triethanolamine enough for pH                                                                         6.5                                                   Purified water enough for                                                                             100.0     g                                           ______________________________________                                    

EXAMPLE XXXVII INJECTIBLE SUSPENSION

Unit formulation for a 2 ml ampul:

    ______________________________________                                        microcrystallized Dexamethasone acetate                                                                 10.0 mg                                             (>80 μm)                                                                   ______________________________________                                    

Suspension solution:

    ______________________________________                                        Polysorbate 80             0.015 g                                            Sodium carboxymethyl cellulose                                                                           0.010 g                                            Sodium chloride            0.010 g                                            Purified water for injection enough for                                                                   2.00 ml                                           ______________________________________                                    

    ______________________________________                                        FIG. 1                                                                        ______________________________________                                        DEE C108B                                                                     Initial temperature:   285.2K                                                 Final temperature:     379.3K                                                 Scanning rate:         2.00    C/mn                                           Amplification range:   1.000   mV                                             Sample mass:           37.200  mg                                             Sampling rate:         2.08    s                                              Storage:               1357    points                                         ______________________________________                                        FIG. 2                                                                        ______________________________________                                        Glass transition determination                                                Temperature range for Tg Determination:                                       Beginning temperature: 61.79   C.                                             End temperature:       66.63   C.                                             The three Glass temperatures are:                                                                    64.0    C.                                                                    64.79   C.                                                                    65.38   C.                                             Cp variation:          6.64    Cal/g C.                                       Integration with a linear base line                                           Peak start:            62.06   C.                                             Peak end:              74.23   C.                                             Onset temperature:     64.89   C.                                             Enthalpy:                                                                              -.27672E + 004 mJ or -.66202E/003 mcal                                        -.74389E + 002 J/g or -.17796E + 002 cal/g                           Endothermic peak                                                              top of peak temperature:                                                                             66.56   C.                                             ______________________________________                                        FIG. 3                                                                        ______________________________________                                        01/08/90                                                                      DEE C114B                                                                     Initial temperature:   285.2K                                                 Final temperature:     525.0K                                                 Scanning rate:         2.00    C/mn                                           Amplification range:   1.000   mV                                             Sample mass:           25.400  mg                                             Sampling rate:         3.68    s                                              Storage:               1955    points                                         Glass transition determination                                                Temperature range for Tg Determination:                                       Beginning temperature: 62.29   C.                                             End temperature:       66.57   C.                                             The three Glass temperatures are:                                                                    64.10   C.                                                                    64.55   C.                                                                    64.98   C.                                             Cp variation:          4.56    Cal/g C.                                       Integration with a linear base line                                           Peak start:            62.16   C.                                             Peak end:              75.38   C.                                             Onset temperature:     64.62   C.                                             Enthalpy:                                                                              -.18837E + 004 mJ or -.45064E/003 mcal                                        -.74161E + 002 J/g or -.17742E + 002 cal/g                           Endothermic peak                                                              top of peak temperature:                                                                             66.44   C.                                             ______________________________________                                        FIG. 4                                                                        ______________________________________                                        07/08/90                                                                      DEE C109                                                                      Initial temperature:   285.2K                                                 Final temperature:     415.2K                                                 Scanning rate:         2.00    C/mn                                           Amplification range:   1.000   mV                                             Sample mass:           42.200  mg                                             Sampling rate:         2.08    s                                              Storage:               1875    points                                         Fin storage:           1875    points in                                                                     file 4                                         Peak start:            61.16   C.                                             Peak end:              73.61   C.                                             Onset temperature:     64.75   C.                                             Enthalpy:                                                                              -.30705E + 004 mJ or -.73458E/003 mcal                                        -.72762E + 002 J/g or -.17407E + 002 cal/g                           Endothermic peak                                                              top of peak temperature:                                                                             66.69   C.                                             Glass transition determination                                                Temperature range for Tg Determination:                                       Beginning temperature: 61.16   C.                                             End temperature:       66.68   C.                                             The three Glass temperatures are:                                                                    63.70   C.                                                                    64.22   C.                                                                    65.24   C.                                             ______________________________________                                        FIG. 5                                                                        ______________________________________                                        DEE C114                                                                      Initial temperature:   285.2K                                                 Final temperature:     415.2K                                                 Scanning rate:         2.00    C/mn                                           Amplification range:   1.00    mV                                             Sample mass:           61.600  mg                                             Sampling rate:         2.08    s                                              Storage:               1875    points                                         Glass transition determination                                                Temperature range for Tg Determination:                                       Beginning temperature: 57.84   C.                                             End temperature:       67.04   C.                                             The three Glass temperatures are:                                                                    63.60   C.                                                                    64.31   C.                                                                    65.52   C.                                             Cp variation:          5.24    Cal/g C.                                       Integration with a linear base line                                           Peak start:            77.00   C.                                             Peak end:              64.78   C.                                             Enthalpy:                                                                              -.45478E + 004 mJ or -.10879E/004 mcal                                        -.73828E + 002 J/g or -.17662E + 002 cal/g                           Endothermic peak                                                              top of peak temperature:                                                                             66.90   C.                                             ______________________________________                                        FIG. 6                                                                        ______________________________________                                        07/08/90                                                                      DEE 109MC                                                                     Initial temperature:   285.2K                                                 Final temperature:     415.2K                                                 Scanning rate:         2.00    C/mn                                           Amplification range:   1.000   mV                                             Sample mass:           35.800  mg                                             Sampling rate:         2.08    s                                              Storage:               1875    points                                         Fin. Storage:          1875    points in                                                                     file 5                                         Integration with a linear base line                                           Peak start:            61.75   C.                                             Peak end:              73.26   C.                                             Onset temperature:     64.65   C.                                             Enthalpy:                                                                              -.26206E + 004 mJ or -.62695E/003 mcal                                        -.73203E + 002 J/g or -.17512E + 002 cal/g                           Endothermic peak                                                              top of peak temperature:                                                                             66.90   C.                                             Glass transition determination                                                Temperature range for Tg Determination:                                       Beginning temperature: 61.65   C.                                             End temperature:       67.04   C.                                             The three Glass temperatures are:                                                                    64.40   C.                                                                    64.57   C.                                                                    65.59   C.                                             Cp variation:          7.48    Cal/g C.                                       ______________________________________                                        FIG. 7                                                                        ______________________________________                                        Ref. 9007033                                                                  Coulter ® LS Particle size analysis A0890.S18                             Filename: A0890.S18      Group ID:  A0-890                                    Sample ID:                                                                              TX 066 LOT 037 MC2                                                                           Run number:                                                                              6                                         Operator: A.P.C. SIMM                                                         Comments: DISPERSION: glycerol & U. SOUND                                               COULTRONICS FRANCE                                                  Start time:                                                                             10:42 25 aug 1990                                                   Run length:                                                                             90 seconds                                                          Obscuration:                                                                            6%                                                                  PIDS Obscur:                                                                            30%                                                                 Optical model:                                                                          Fraunhofer PIDS included                                            PC:       Version 1.10 13:07 Fri Mar 02 1990                                            Volume Statistics (Arithmetic) 10890.S18                            Calculations                                                                           0.10 μm to 834.40 μm                                           from                                                                          Volume   100.0   %                                                            Mean     22.49  μm  95% Conf.                                                                             19-42-25-56                                                                            μm                                                        limits:                                                Median   19.72  μm  Std. Dev:                                                                             15-67    μm                                 Mean/median                                                                            1.341         Variance:                                                                             245.5    μm.sup.2                           Ratio                                                                         Mode     29.60  μm  Coef. var:                                                                            69.66    %                                                  Skewness:                                                                             7.016e-001 Right                                                                         skewed                                                     Kurtois:                                                                              -1.088e-001                                                                              Platy-                                                                        kurtic                                        %        10.00     25.00  50.00   75.00                                                                              90.00                                  Size μm                                                                             45.20     32.64  19.72   10.10                                                                              3.771                                  ______________________________________                                        FIG. 8                                                                        ______________________________________                                        DATA TREATMENT OF A CURVE STDRED: SCANNING                                    MODE: INTEGRATION, CRYSTALLINITY AND GLASS                                    TRANSITION DETERMINATIONS                                                     11/04/90                                                                      THERAMEX A                                                                    Initial temperature: 290.2K                                                   Final temperature:   525.2K                                                   Scanning rate:       2.00    C/mn                                             Amplification range: 10.00   mV                                               Sample mass:         51.300  mg                                               Sampling rate:       1.92    s                                                Storage:             3671    points                                           Glass transition determination                                                Temperature range for Tg Determination:                                       Beginning temperature: 172.9       C.                                         End temperature:       181.5       C.                                         The three Glass temperatures are:                                                                    176.9       C.                                                                178.7       C.                                                                179.9       C.                                         Pente = :              -13.2346027168                                         Integration with a linear base line                                           Peak start:            173.9       C.                                         K1 =                   2.490                                                  S(K.sub. 1) =          -3.1655                                                Peak end:              191.1       C.                                         K2                     2760                                                   S(K.sub.2)             -3.1354                                                Enthalpy:                                                                              -3.487E + 003 mJ or -1.626E/001 mcal                                          or -6.797E + 001 J/g                                                 Endothermic peak                                                              TP =                   181.881617                                             top of peak temperature:                                                                             180.1       C.                                         11/04/90                                                                      THERAMEX B                                                                    Initial temperature:                                                                              290.2K                                                    Final temperature:  525.2K                                                    Scanning rate:      5.00     C/mn                                             Amplification range:                                                                              2.500    mV                                               Sample mass:        15.600   mg                                               Sampling rate:      .80      s                                                Storage:            3524     points                                           Integration with a linear base line                                           Peak start:         169.6    C.                                               K1                  2356                                                      S(K.sub.1)          -2.3444                                                   Peak end:           199.5    C.                                               K2                  2806                                                      S(K.sub.2)          -1.8524                                                   Enthalpy:                                                                              -1.052E + 003 mJ or -1.618E/001 mcal                                          -6.748E + 001 J/g                                                    Endothermic peak                                                              TP =                   181.919107A6                                           top of peak temperature:                                                                             180.2      C.                                          Glass transition determination                                                Temperature range for Tg Determination:                                       Beginning temperature: 169.5       C.                                         End temperature:       181.5       C.                                         The three Glass temperatures are:                                                                    176.4       C.                                                                178.1       C.                                                                179.5       C.                                         Pente:                 -6.4818199304                                          ______________________________________                                        FIG. 9                                                                        ______________________________________                                        11/04/90                                                                      THERAMEX C                                                                    Initial temperature:                                                                              290.2K                                                    Final temperature:  525.2K                                                    Scanning rate:      5.00     C/mn                                             Amplification range:                                                                              2.500    mV                                               Sample mass:        10.500   mg                                               Sampling rate:      .80      s                                                Storage:            3524     points                                           Integration with a linear base line                                           Peak start:            173.6      C.                                          K1                     2417                                                   S(K.sub.1)             -1.7128                                                Peak end:              199.5      C.                                          K2                     2807                                                   S(K.sub.2)             -1.4299                                                Enthalpy:                                                                              -7.215E + 002 mJ or -1.644E/001 mcal                                          or -6.872E + 001 J/g                                                 Endothermic peak                                                              TP =                   180.985774333                                          top of peak temperature:                                                                             179.2       C.                                         Glass transition determination                                                Temperature range for Tg Determination:                                       Beginning temperature: 173.5       C.                                         End temperature:       180.5       C.                                         The three Glass temperatures are:                                                                    177.2       C.                                                                178.9       C.                                                                179.4       C.                                         Pente:                 -11.8392024107                                         THERAMEX D                                                                    Initial temperature:                                                                              290.2K                                                    Final temperature:  525.2K                                                    Scanning rate:      5.00     C/mn                                             Amplification range:                                                                              2.500    mV                                               Sample mass:        15.900   mg                                               Sampling rate:      .80      s                                                Storage:            3524     points                                           Integration with a linear base line                                           Peak start:         175.5    C.                                               K1                  2446                                                      S(K.sub.1 )         -2.4676                                                   Peak end:           194.5    C.                                               K2                  2731                                                      S(K.sub.2)          -2.3127                                                   Enthalpy:                                                                              -1.114E + 003 mJ or -1.677E/001 mcal                                          or -7.011E + 001 J/g                                                 Endothermic peak                                                              TP                     181.252441                                             top of peak temperature:                                                                             179.0       C.                                         Glass transition determination                                                Temperature range for Tg Determination:                                       Beginning temperature: 173.5       C.                                         End temperature:       181.0       C.                                         The three Glass temperatures are:                                                                    178.0       C.                                                                179.1       C.                                                                179.7       C.                                         Pente:                 -21.4280794192                                         ______________________________________                                        FIG. 11                                                                       ______________________________________                                        Ref. 9007032                                                                  COULTER ® LS Particle size analysis A0889.S01                             Filename: A0889.S01      Group ID:  A0-889                                    Sample ID:                                                                              TX 066 LOT 037 MC1                                                                           Run number:                                                                              1                                         Operator: A.P.C SIMM                                                          Comments: DISPERSION: NONIDET & U. SOUND                                                COULTER FRANCE                                                      Start time:                                                                             11.55 24 aug 1990                                                   Run length:                                                                             91 seconds                                                          Obscuration:                                                                            5%                                                                  PIDS Obscur:                                                                            23%                                                                 Optical model:                                                                          Fraunhofer PIDS included                                            PC:       Version 1.10 13:07 Fri Mar 02 1990                                            Volume Statistics (Arithmetic) 10889.S01                            Calculations                                                                           0.10 μm to 834.40 μm                                           from                                                                          Volume   100.0  %                                                             Mean     32.93  μm  95% Conf.                                                                             29-02-26-84                                                                            μm                                                        limits:                                                Median   31.12  μm  Std. Dev:                                                                             18-96    μm                                 Mean/median                                                                            1.058         Variance:                                                                             396.4    μm.sup.2                           Ratio                                                                         Mode     44.70  μm  Coef. var:                                                                            60.61    %                                                  Skewness:                                                                             3.640e-001 Right                                                                         skewed                                                     Kurtois:                                                                              -5.857e-001                                                                              Platy-                                                                        kurtic                                        %        10.00     25.00  50.00   75.00                                                                              90.00                                  Size μm                                                                             65.21     47.02  31.12   17.07                                                                              7.810                                  ______________________________________                                        FIG. 12                                                                       ______________________________________                                        Operator: FP        Sample:    MC2                                            16 Oct. 1991                   16:03                                          Field area:                                                                             30543.81  Calibration:                                                                             0.2717 mcm/pixel                               Field 1:            Class 2:                                                  Feat.    Area       Perimeter Long dimsn.                                     ______________________________________                                        1        60.181     34.189    13.055                                          2        96.954     38.947    14.827                                          3        45.634     26.169    9.2551                                          4        69.116     33.109    12.772                                          5        58.409     30.959    12.107                                          6        53.277     29.411    10.818                                          7        37.807     28.331    12.375                                          8        49.732     29.488    11.273                                          9        59.295     29.303    10.788                                          10       48.292     27.650    9.6381                                          11       49.474     27.094    10.229                                          12       39.727     27.849    11.145                                          13       57.818     31.689    11.848                                          14       32.490     24.579    9.6381                                          15       44.231     25.782    9.4914                                          16       29.832     22.428    7.9550                                          17       102.086    40.780    15.910                                          18       46.188     30.739    13.058                                          19       47.443     30.379    12.261                                          20       50.877     28.224    10.233                                          Total    1078.86    597.098   228.675                                         Mean     53.943     29.855    11.434                                          St Dev.  18.281     4.4267    1.9422                                          ______________________________________                                        FIG. 13                                                                       ______________________________________                                        N.M.A. 028-028B 031-031B                                                      028001.DT3                                                                            05-30-1991                                                                              13:50:40                                                    Y-scale 008 AU/FS Sample name   tx(1-00-1)                                    Sampling                                                                              21 msec *4                                                                              Paper speed   4 mm/min                                      time                                                                          Sense   normal                                                                Resolu- 3 nm      Column ultrosphere DDS 4,6 mm                               tion              ID $250 mm                                                  Time    2.4-25 min                                                                              Packing material C18                                        range                                                                         Interval                                                                              1 sec     Mobile phase Acetonitrile 360                               Baseline                                                                              OFF       Flow     MeOH 240                                                                              1,3   ml/min                                                 rate                                                        Smooth- 5 points  Pressure 2.300 psi                                          ing                                                                           Drift   .002      Slope    H.sub.2 O 400                                                                         .0001 AU/                                          AU/min                           min                                  Width   .001 min  Height           .0002 AU                                   Time    30 min    Min. area        .00002                                                                              AU*                                  double                                   min                                                    Minus                  OFF                                                    peak                                                        ______________________________________                                    

What is claimed is:
 1. A process for crystallizing a product comprisinga pharmaceutically active ingredient of steroidal structure to obtainwithout any mechanical procedure a homogenous class of product which maybe prepared beforehand comprising dissolving the product to becrystallized in a ternary mixture of a lipophilic solvent, a hydrophilicsolvent and a surface active agent at a temperature close to the boilingpoint of the ternary mixture, allowing the ternary mixture to cool to atemperature where crystallization occurs and recovering the resultingcrystals.
 2. A process according to claim 1 wherein the activeingredient is an estrane derivative.
 3. A process according to claim 2wherein the estrane derivative is selected from the group consisting ofestradiol, estrone, estriol, 19-nor Testosterone, the 3-mono ethers ofthe same, the 3, 17-diethers of these compounds and the esters of thesecompounds.
 4. A process according to claim 1 wherein the activeingredient is an androstane derivative.
 5. A process according to claim4 wherein the derivative of androstane is selected from the groupconsisting of Testosterone, ethers of Testosterone, esters ofTestosterone, Testosterones substituted by a halogen or a lower alkyl inposition 4, 6, 7 or 16 and the 17α-ethynyl-17β-acetoxy-5α-androst-2-ene.6. A process according to claim 1 wherein the active ingredient is apregnane derivative.
 7. A process according to claim 6 wherein thepregnane derivative is a steroidal compound selected from the groupconsisting of progesterone, enolic ethers of progesterone, cyclic orlinear enamines of progesterone, 17α-hydroxy progesterones, esters of17α-hydroxy progesterone, progesterones substituted by an alkyl, atrifluoromethyl or a halogen in position 1,6,7 and/or 16 and the ethersor esters thereof.
 8. A process according to claim 1 wherein the activeingredient is a 19-nor pregnane derivative.
 9. A process according toclaim 8 wherein the derivative of 19-nor pregnane is a steroidalderivative selected from the group consisting of17α-hydroxy-19-nor-progesterone, the ethers in position 17 of17α-hydroxy-19-nor-progesterone,6-methyl-17α-hydroxy-19-nor-progesterone, ethers in position 17 of6-methyl-17α-hydroxy-19-nor-progesterone, esters in position 17 of6-methyl-17α-hydroxy-19-nor-progesterone,6-methyl-3,20-dioxo-17α-hydroxy-19-nor-pregna-4,6-diene and the estersin position 17 of 6-methyl-17α-hydroxy-19-nor-pregna-4,6-diene and the17α- and 21-methyl or ethyl analogs of6-methyl-3,20-dioxo-19-nor-pregna-4,6-diene.
 10. A process according toclaim 1 wherein the active ingredient is a derivative of cholestane. 11.A process according to claim 1 wherein the active ingredient is aderivative of 21-hydroxy Δ4-pregnene.
 12. A process according to claim10 wherein the 21-hydroxy Δ4-pregnenic derivative is a corticosteroidselected from the group consisting of Cortisone, Prednisone,Dexamethasone, Betamethasone, Triamcinolone, Medrol, Cortivazol, theiresters in position 17, their diesters in positions 17 and 21 and theiresters in position
 21. 13. A process according to claim 1 wherein thelipophilic solvent is selected from the group consisting of alkanols,ketones, alkyl esters and cyclic ethers in which the hydrophilic solventhas to be miscible in an amount up to 12%.
 14. A process according toclaim 13 wherein the hydrophilic solvent is selected in such a manner tobe miscible with the lipophilic solvent in order to insure a homogeneoussolution.
 15. A process according to claim 13 wherein the hydrophilicsolvent is an aqueous mixture made of one or several oxygenatedsolvents.
 16. A process according to claim 13 wherein the hydrophilicsolvent is selected from the group consisting of water and/or polarsolvents and/or lower alkyl esters of cycloalkylcarboxylates.
 17. Aprocess according to claim 1 wherein the surface active agent is ananionic surfactive agent.
 18. A process according to claim 17 whereinthe anionic surfactive agent is soluble in the lipophilic solvent or inthe hydrophilic solvent and necessarily at the same time in the mixtureof both solvents.
 19. A process according to claim 1 wherein the anionicsurface active agent is selected from the group consisting of thepolyoxyethylenic esters of sorbitan and fatty acids, having at least 8carbon atoms the polyoxyethylenic esters of stearic acid and thecopolymers of ethylene oxide and propylene oxide.
 20. A processaccording to claim 1 wherein the ternary mixture, made of a lipophilicsolvent, a hydrophilic solvent and a surface active agent, is realizedin one or several steps.
 21. A process according to claim 1 wherein theconcentration of the surface active agent in the ternary mixture liesbetween 0.01 and 10%.
 22. A process according to claim 21 wherein theconcentration in surface active agent in the ternary mixture liesbetween 0.05 and 5%.
 23. A process according to claim 1 wherein theternary mixture containing the active ingredient to be crystallized, isheated to a temperature as close as possible to the boiling point of themixture of solvent in order to insure the highest possible concentrationof the compound to be crystallized and to decrease the temperature ofcrystallisation of the said compound.
 24. The microcrystallized productsof the process according to claim 1.